The present invention is generally related to a drug delivery, and more particularly related to a liposome composition for delivery of a therapeutic agent to eyes in patients.
Eye diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) that occur at the back of eyes are the leading causes of blindness in the elderly and many productive individuals in the developed country (Aiello, L. M. (2003) Am. J. Ophthalmol. 136, 122-135; Klein, R. et al. (1992) Ophthalmology 99, 933-943). Neovascularization or formation of new blood vessels, in retinal or choroidal tissues is a central feature of these diseases. This pathological angiogenesis causes visual loss through increased vascular permeability leading to retinal edema, vascular fragility resulting in intraocular hemorrhage, or fibro-vascular proliferation with tractional and rhegmatogenous retinal detachment (Ferris, F. L. et al. (1984) Arch Ophthalmol. 102, 1640-1642; Archer, D. B. (1999) Eye 13, 497-523). The current accepted treatments for these diseases including thermal laser photocoagulation and photodynamic therapy provided clinical benefits but are associated with significant adverse effects (Early Treatment Diabetic Retinopathy Study Research Group (1991) Ophthalmology 98, 766-785; Ciulla, T. A. et al. (1998) Surv. Ophthalmol. 43, 134-146; Verteporfin In Photodynamic Therapy Study Group (2001) Am. J Ophthalmol. 131, 541-560). Moreover, these treatments are associated with high rates of persistent and recurrent disease accompanied by an increased frequency of severe visual loss (Macular Photocoagulation Study Group (1986) Arch. Ophthalmol. 104, 503-512; Macular Photocoagulation Study Group (1994) Arch. Ophthalmol. 112, 489-499). A large number of new therapies have focused on pharmacological agents that inhibit the process of angiogenesis (Das, A. et al. (2003) Retinal and Eye Research 22, 721-748). For an effective therapy, it is essential that a therapeutic concentration of the pharmacological agent to be present at the disease site for an extended period of time.
Eye is an enclosed organ of the body. The blood circulation through the eye is slower than the rest of the body. Delivery of an effective dose of the drug to the eye, particularly the rear end of the eye, such as retinal or choroidal tissues, remains a difficult task. Current methods for ocular drug delivery include topical administration (eye drops), systemic administration (oral or intravenous), subconjunctival injection, periocular injection, intravitreal injection, and surgical implant. However, all these methods have limitations in delivering drugs to the back of the eye. The tissues of the lens, sclera, vitreous, etc. prevent drugs from readily moving from the front of the eye to the back when the topical eye drops are used. The systemic route of drug delivery following oral or intravenous administration has limitations as the drug may not reach the target tissues at an optimal concentration without the risk of systemic toxicities. Intravitreal injections, periocular injections, and sustained-release implants can be used to achieve therapeutic levels of drugs in ocular tissues, but invasive methods are inherently risky due to the potential for bleeding, infection, retinal detachment, and other local injuries.
Liposome and lipid/drug complex have been widely studied and employed as vehicles for intravenous administration of therapeutic agents. Liposome is a spherical, self-enclosed vesicle composed of amphipathic lipids. Therapeutic agents can be encapsulated in the aqueous compartment or intercalated into the lipid bilayer of the vesicle (Szoka, F. Jr. and Papahadjopoulos, D. (1980) Ann. Rev. Biophys. Bioeng. 9, 467-508). The lipid/drug complex, on the other hand, is formed by hydrophobic-hydrophobic or/and electrostatic charge-charge interactions between the lipids and drugs, such as lipid : amphotericin B complexes (Janoff, A. S. et al. (1988) Proc. Natl. Acad. Sci. USA. 85, 6122-6126; Guo, L. S. S. et al. (1991) In. J. Pharm. 75, 45-54) and lipid : nucleic acid complexes described in U.S. Pat. Nos. 6,071,533 and 6,210,707 B1. Studies have shown that these micro-or nano-particles can decrease the toxicity and enhance the efficacy of several anticancer and antifungal drugs (Gabizon, A. A. (1992) Cancer Res. 52, 891-896; Northfelt, D. W. et al. (1998) J. Clin. Oncol. 16, 2445-2451; Oppenheim, B. A. et al. (1995) Clin. Infect. Dis. 21, 1145-1153). In particular, the so-called long circulating liposome includes a surface coat of soluble polymer chains, which act to prevent in vivo uptake by mononuclear phagocytic system (Allen, T. M. et al. (1991) Biochim. Biophys. Acta 1066, 29-36; Chonn, A. et al. (1992) J. Biol. Biochem. 267, 18759-18765; U.S. Pat. No. 5,013,556). The therapeutic benefit associated with the long-circulating liposomes is believed to relate to increase delivery of drug in disease tissues such as tumors (Papahadjopoulos, D. et al. (1991) Proc. Natl. Acad. Sci. USA. 88, 11460-11464; U.S. Pat. No. 5,213,804) and sites of infection (Bakker-Woudenberg, IAJM et al. (1993) J. Infect. Dis. 168, 164-171; U.S. Pat. No. 5,356,633) and inflammation (Rosenecker, J. et al. (1996) Proc. Natl. Acad. Sci. USA. 93, 7236-7241; U.S. Pat. No. 5,843,473).
Several methods/systems have been disclosed for delivering material encapsulated in liposome to the eye through the blood stream. U.S. Pat. No. 4,891,041 describes a method of selectively and repetitively releasing a material at a specific site in the blood stream inside the body of an animal, including the eye. The method uses a heat-sensitive lipid vesicle comprising a specific lipid composition. Following injecting the lipid vesicles into the blood stream, a laser beam is applied to trigger the release of the encapsulated material at the specific site of the tissue. U.S. Pat. No. 6,074,666 and US 2003/0087889 disclosed a liposome composition of porphyrin photosensitizers for photodynamic therapy in treating occult choroidal neovascular lesions in AMD patients. The liposomal photosensitizer is given by intravenous injection and followed by applying laser light to the eye to sensitize the photosensitizer. However, as shown in FIG. 1 A, most of the administered hydrophobic porphyrin compound separates from the liposome in the blood stream and incorporates into plasma lipoproteins which subsequently serve as an endogenous vehicle to transport the porphyrin compound to the target tissues (U.S. Pat. No. 5,214,036). It is known that hydrophobic or amphipathic drugs encapsulated in liposomes have the tendency to release from the liposome in the presence of blood or blood components (Wasen, K. M. et al. (1993) Antimicrob. Agent Chemother. 37, 246-250). Depending upon the chemical nature of the drug, the released drug may remain in free form in the blood circulation or incorporate into the surrounding plasma lipoproteins and proteins. Due to dilution and distribution into the body pool as well as elimination by renal filtration, the amounts of drug that can be delivered to the target tissues, particularly to the eye tissues with a free drug formulation or an unstable leaky liposome formulation are extremely limited.